Bruton's Tyrosine Kinase (Btk) is a member of the Tec family of tyrosine kinases, and is a regulator of early B-cell development as well as mature B-cell activation, signaling, and survival (T. Hunter, Cell 1987 50:823-829). Inhibition of Btk activity can be useful for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases such as: SLE, rheumatoid arthritis (Whang et al (2014) Drug Discovery Today 19(8):1200-1204; Kim et al (2011) Bioorganic & Med. Chem. Letters 21:6258-6263), multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, and asthma (Di Paolo et al (2011) Nature Chem. Biol. 7(1):41-50; Liu (2011) Drug Metab. and Disposition 39(10):1840-1849; Liu et al (2011) Jour. of Pharm. and Exper. Ther. 338(1):154-163; Lou et al (2012) J. Med. Chem. 55(10):4539-4550; Xu D. et al (2012) Jour. Pharm. and Exp. Ther. 341(1):90-103). In addition, Btk has been reported to play a role in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49); thus, inhibition of Btk activity can be useful for cancer, as well as the treatment of B-cell lymphoma, leukemia, and other hematological malignancies (U.S. Pat. No. 7,514,444; Feldhahn et al. J. Exp. Med. 2005 201:1837).
Certain Btk-modulating compounds possess a tricyclic lactam substructural motif (U.S. Pat. No. 8,618,107; U.S. Pat. No. 8,729,072; U.S. Pat. No. 8,716,274; U.S. Pat. No. 8,722,676). The tricyclic lactam group of these compounds binds in the “H3 binding pocket”. Modification of groups that bind in the H3 pocket can impart selective Btk modulating effects.
As reported by Di Paolo et al (2011) Nature Chem. Biol. 7(1):41-50, “this binding event induces a conformational change in Btk relative to the Apo structure (pdb 3P08) resulting in a Src-like inactive conformation of the kinase domain. This includes rearrangement of Y551 by ˜18 Å from an extended, solvent exposed position to a buried conformation.” This rearrangement and the inability for other kinases to adopt this confirmation imparts selectivity to certain Btk inhibitors.